Contact

If you experience any problems with duoHMM, before
emailing the mail list please:

Make sure you are using the latest version since your
problem may have already been fixed

Check carefully the screen output and the log file. The
problem may be reported here since they both contain many
details about what is going on.

If the problem persists, ask your question on the OXSTATGEN
mailing list and we will be happy to answer!

Options

Here is a list of the command line option for duoHMM

Option [short version]

Description

--haps [-H]

SHAPEIT2 haplotype file

--input-gen [-M]

genetic map file in SHAPEIT2/Impute format

--output-hap [-O]

output pedigree corrected haplotypes this file

--output-generr [-G]

output possible genotyping errors to this file

--output-rec [-R]

output recombination map for pedigree to this file

Examples

Data quality control

We assume your data is in plink binary format with the
pedigree relationships specified in the respective plink .fam
file as plink provides useful pedigree functionality. Before
phasing, genotypes that are inconsistent with Mendelian
inheritance should be removed. High rates of Mendel
inconsistencies are likely to indicate an incorrect family
relationship. The plink
website provides details on how to investigate Mendel
consistency within families.

Once you are confident that all your family relationships are
correct. Simply run this plink command to remove any Mendel
inconsistencies:

Phasing with SHAPEIT2

We simple run SHAPEIT2 using the --noped flag so that
the pedigree relationships are completely ignored. We have also
found it to be (slightly) advantageous to use a larger than
default window when large amounts of IBD sharing are present
hence we use the -W 5 here:

This produces duohmm-example-corrected.haps which is a
standard SHAPEIT2 format haplotype file that has been
corrected for pedigree structure. An additional benefit is that
a child's haplotypes are now ordered with the paternal haplotype
first and the maternal haplotype second.

NOTE : this feature has
been built into the SHAPEIT software (via the --duohmm
flag). So if you just want to create a set of pedigree-correct
haplotypes then we would advise you to use that option. See here
for more details.

Detecting subtle genotyping errors with duoHMM

Not all genotyping errors will produce a Mendelian
inconsistency. duoHMM can identify genotypes that are
unlikely within a duo/trio based on patterns of recombination.
Likely genotyping errors can be detected by running the command:

Markers with high probability are likely to be erroneous in
either the parent or the child (or both), it is not possible to
distinguish which individual contained the error.

Detecting recombination crossovers with DuoHMM

Detecting crossover events is more complicated as we need to
integrate over the uncertainty in phase. To do this, we need to
simulate haplotypes from the SHAPEIT2 diploid graph
which is output by the --output-graph argument
(we included this earlier in our phasing example).

We now will:

Simulate ten haplotype sets from the SHAPEIT2 graph
with different seeds

Calculate the recombination map each meiosis in the
haplotype sets using duoHMM

The first two columns are the parent and child involved in the
meisosis, the START and END columns are the regions where a
crossover may have occurred (flanking heterozygote sites on the
parents) and the final column is the probability of a crossover
event occurring.

Note: this routine has been shown to have good specificity,
that is it has low false positive rate when a high probability
threshold is used. The power to detect recombination events is
very dependendant on the structure of the pedigree. For example,
in a nuclear family with >2 siblings most crossover events
should be detectable. Pedigrees with such structure are informative
towards recombination.

We have also demonstrated some power to detect crossovers in uninformative
meisoses, however this is very dependant on how much more
distant IBD sharing is present in a cohort.